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Synthesis of Peptides and Pyrazines from -Amino Alcohols through Extrusion of H2 Catalyzed by Ruthenium Pincer Complexes Ligand-Controlled Selectivity.

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DOI: 10.1002/anie.201105876
Homogeneous Catalysis
Synthesis of Peptides and Pyrazines from b-Amino Alcohols through
Extrusion of H2 Catalyzed by Ruthenium Pincer Complexes: LigandControlled Selectivity**
Boopathy Gnanaprakasam, Ekambaram Balaraman, Yehoshoa Ben-David, and
David Milstein*
Peptides constitute one of the most important families of
compounds in chemistry and biology. Short peptides have
found intriguing biological and synthetic applications. For
example, the conformational rigidity of cyclic peptides makes
them attractive for drug discovery and biomedical research.[1]
Several cyclic peptides that show intriguing biological activity
are found in nature.[2] Cyclic peptides have been discovered
that are novel antibiotics,[3] enzyme inhibitors,[4] and receptor
antagonists. Among them are the smallest cyclopeptides, 2,5diketopiperazines derivatives, which are commonly found as
natural products.[5] These compounds exhibit high-affinity
binding to a large variety of receptors and show a broad range
of biological acitivities,[6] including antimicrobial, antitumoral, antiviral, and neuroprotective effects. 2,5-diketopiperazine derivatives are synthesized in solution or on the solid
phase from commercially available and appropriately protected chiral a-amino acids in processes that are usually not
atom-economical and generate considerable amounts of
waste. Large libraries of cyclic peptides are accessible through
solid-phase split-and-pool synthesis,[7] and various methods
were developed for their syntheses.[8] Very recently, the
synthesis of diketopiperazines from amino acids under
microwave irradiation was reported.[9] Green, atom-economical methods for the generation of peptides are highly
We have developed several reactions catalyzed by PNN
and PNP RuII pincer complexes based on pyridine,[10, 11]
bipyridine,[12, 13] and acridine[14] and have discovered a new
mode of metal–ligand cooperation[15] based on ligand aromatization–dearomatization.[16] For example, the PNN RuII
pincer complex 1 (Scheme 1) catalyzes the direct synthesis
of amides from alcohols and amines with liberation of H2[17]
(Scheme 2, Eq. (1)). Several reports on amide formation by
[*] Dr. B. Gnanaprakasam, Dr. E. Balaraman, Y. Ben-David,
Prof. D. Milstein
Department of Organic Chemistry
Weizmann Institute of Science
76100 Rehovot, (Israel)
[**] This research was supported by the European Research Council
under the FP7 framework, (ERC No 246837), by the Israel Science
Foundation, and by the MINERVA Foundation. D.M. is the holder of
the Israel Matz Professorial Chair of Organic Chemistry.
Supporting information for this article is available on the WWW
Scheme 1. PNN- and PNP-type pincer ruthenium complexes.
Scheme 2. Reactions of alcohols with amines catalyzed by complexes
dehydrogenative coupling of amines with alcohols appeared
later.[18] Unlike complex 1, the analogous PNP complex 2 (or
complex 3 in the presence of an equivalent of base) catalyzes
the coupling of amines with alcohols to form imines rather
than amides with liberation of H2 and H2O (Scheme 2,
Eq. (2)).[19]
Herein we report a novel method for peptide synthesis,
which involves dehydrogenative coupling of b-amino alcohols
with extrusion of H2 catalyzed by complex 1. This environmentally benign and atom-economical reaction proceeds
under neutral reaction conditions without the use of toxic
reagents, activators, condensing agents, or other additives.
With the analogous PNP complex 2, a strikingly different
reaction takes place, which leads to pyrazines with extrusion
of H2 and H2O.
Initially, we were interested to see whether coupling of bamino alcohols with amines can be accomplished and whether
racemization would be involved. Reaction of (S)-2-amino-3phenylpropan-1-ol (4), benzylamine, and 1 mol % of the
catalyst 1 in toluene at reflux for six hours led to (S)-2-aminoN-benzyl-3-phenylpropanamide 5 in 58 % yield[20a] after
column chromatography (Scheme 3). The specific rotation
of amide 5 obtained from the catalysis is essentially the same
as reported[20b] (+ 16.08). The neutral reaction conditions
likely help to prevent racemization.
2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 12240 –12244
Table 1: Synthesis of cyclic dipeptides from b-amino alcohols catalyzed
by complex 1.[a]
Scheme 3. Amidation of (S)-2-amino-3-phenylpropan-1-ol (4) with benzylamine catalyzed by 1.
Scheme 4. Peptide formation by dehydrogenative coupling of b-amino
Next, we explored the self-reactions of b-amino alcohols.
In principle, dehydrogenative coupling of b-amino alcohols
can lead to formation of both cyclic and linear peptides
(Scheme 4). Heating a 1,4-dioxane solution containing (S)(+)-2-amino-1-propanol (2 mmol) and 1 (1 mol %) to reflux
for 19 h in argon atmosphere resulted in 90 % conversion of
the amino alcohol, as determined by GC–MS. Solvent
evaporation, dilution of the residue with CH2Cl2, separation
of an insoluble solid by filtration, and drying under vacuum
gave 72 % poly(alanine) 6 (R = Me in Scheme 4) containing a
minor quantity of the cyclic dimer 3,6-dimethylpiperazine2,5-dione 7 a[21] (R = Me in Scheme 4, Table 1, entry 1). The
products were characterized by NMR spectroscopy and mass
spectrometry. The characteristic peak at 174.9 ppm in the
C{1H} NMR spectrum of 6 indicates the presence of a
carbonyl group. The specific rotation of the product in acetic
acid was 1058. The ESI mass spectrum revealed the
formation of a linear polypeptide sequence. The peak with
the highest mass-to-charge ratio found by MALDI-TOF
spectrometry was at m/z 1644, which corresponds to 23
monomer units (see the Supporting Information).
Interestingly, larger substituents in a-position to the
amine group lead to the formation of the corresponding
cyclic dipeptides as the only products under the same reaction
conditions. Thus, a 1,4-dioxane solution of (S)-2-amino-4methylpentan-1-ol heated to reflux with complex 1 (1 mol %)
led to isolation of the cyclic dipeptide 3S,6S-3,6-diisobutylpiperazine-2,5-dione (7 b) in 64 % yield after workup
(Table 1, entry 2).[22] The product structure was confirmed
by NMR spectroscopy and mass spectrometry (see the
Supporting Information). The optical rotation (½a20
D ¼478)
was very close to the reported value (438), thus indicating
Angew. Chem. Int. Ed. 2011, 50, 12240 –12244
b-Amino alcohol
Yield[b] [%]
[a] Complex 1 (0.02 mmol), amino alcohol (2 mmol), and 1,4-dioxane
(2 mL) were heated to reflux in argon (oil bath temperature of 135 8C) for
19 h. [b] Yield of isolated product. [c] Including a minor amount of the
dipeptide 7 a.
that no racemization had taken place.[23] A lower yield of 7 b
(52 %) was obtained in toluene as a solvent. Similarly, the use
of benzene as a solvent resulted in 48 % yield after 26 h. The
melting point of the cyclic dipeptide 7 b was 272 8C, as
In contrast to traditional peptide syntheses, which include
both solid- and solution-phase methods and produce waste,
during this reaction only H2 is formed as a by-product.
Activated esters or carboxylic acids or the use of microwave
conditions are not required.
To explore the synthetic utility of this reaction, various bamino alcohols were studied. A 1,4-dioxane solution containing (2S,3S)-2-amino-3-methylpentan-1-ol (2 mmol) and catalyst 1 (0.02 mmol) was heated to reflux for 19 h and then
cooled to room temperature; subsequently the solid product
precipitated, was filtered off, and was dried under vacuum to
give pure 3-(sec-butyl)-6-(sec-butyl)piperazine-2,5-dione 7 c
in 72 % yield (Table 1, entry 3). The structure was confirmed
by NMR spectroscopy and mass spectrometry. Under the
same conditions, (S)-2-amino-3-methylbutan-1-ol yielded an
2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
insoluble solid, which precipitated from the reaction mixture
and was isolated by filtration and dried under vacuum to give
78 % of (3S,6S)-3,6-diisopropylpiperazine-2,5-dione 7 d
(Table 1, entry 4). The optical rotation of the pure product
(528) was essentially the same as reported[24] (54.88). Thus,
under the described experimental conditions, no racemization
took place.
The reaction of (S)-2-amino-3-phenylpropan-1-ol and 1 in
1,4-dioxane at reflux led to 90 % conversion and isolation of
(3S,6S)-3,6-dibenzylpiperazine-2,5dione[24] 7 e in 72 % yield without racemization (Table 1,
entry 5 and the Supporting Information). The reaction of 2amino-2-methylpropan-1-ol under the same conditions gave
100 % conversion with isolation of the corresponding cyclic
dipeptide 3,3,6,6-tetramethylpiperazine-2,5-dione 7 f in 92 %
yield (Table 1, entry 6).
Tricyclic ring systems represent an important structural
motif in many naturally existing alkaloids. Such a ring system
was readily achieved when (S)-pyrrolidin-2-yl-methanol was
employed in the new cyclopeptidation reaction. Thus, heating
a 1,4-dioxane solution of (S)-pyrrolidin-2-yl-methanol at
reflux in the presence of catalyst 1 led to 100 % conversion
of the starting material as determined by GC–MS. After
solvent evaporation and subsequent hexane addition to the
crude solid, the solid was isolated by filtration and washed
with hexane to give optically pure (5aS,10aS)-octahydrodipyrrolo[1,2-a:1’,2’-d]pyrazine-5,10-dione[23] 7 g in 99 % yield
(Table 1, entry 7).
Pyrazines are biologically important organic compounds
and their synthesis[25] is of industrial significance. Interestingly, when RuII PNP complex 2 or 3 in the presence of an
equivalent amount of base was used as catalyst, an entirely
different reaction took place, which led to pyrazine derivatives of b-amino alcohols rather than to diketopiperazines
(Scheme 5). Thus, a toluene solution of isoleucinol with
Scheme 5. Synthesis of pyrazines from b-amino alcohols.
complex 2 (1 mol %) was heated to vigorous reflux in argon
for 24 h, while the reaction progress was monitored by GC–
MS, which showed complete conversion of isoleucinol. The
solvent was evaporated under vacuum and the residue was
purified by silica-gel column chromatography to afford 2,6diisobutylpyrazine 8 a in 53 % yield (Table 2, entry 1). In
refluxing 1,4-dioxane, 40 % conversion of the starting material was observed, yielding 15 % of the product 8 a after 24 h.
The 1H NMR spectrum exhibits the characteristic aromatic
CH signals at 8.27 ppm, and GC–MS confirms the expected
molecular weight. The same reaction conducted in open air
atmosphere in the presence of complex 2 resulted in isolation
of 8 a in 48 % yield. The reaction of isoleucinol in air using
complex 3 in the presence of one equivalent of base (relative
Table 2: Synthesis of pyrazines from b-amino alcohols catalyzed by
complex 2.[a]
b-Amino alcohols
Yield[b] [%]
[a] Complex 2 (0.02 mmol), an amino alcohol (2 mmol), and toluene
(2 mL) were heated at vigorous reflux (oil bath temperature 165 8C for
24 h). [b] Yield of isolated product. [c] Reaction performed in air (see the
Supporting Information for details). [d] Heated in absence of solvent (oil
bath temperature at 165 8C).
to Ru) under the same reaction conditions resulted in
isolation of 8 a in 50 % yield. The similar yields of 8 a obtained
after reaction in argon and in air indicate that air does not
play a role as oxidant in the dehydrogenation of the presumed
intermediate 1,4-dihydropyrazine to form the pyrazine. Significantly, no cyclic dipeptide was obtained under these
conditions. Similar results were obtained with other amino
alcohols. Thus, toluene solutions of (S)-2-amino-3-methylbutan-1-ol, (S)-2-amino-4-methylpentan-1-ol, and (S)-2-amino2-phenylethanol were heated at vigorous reflux (bath temperature 165 8C) for 24 h while the reaction progress was
monitored by GC–MS. After complete disappearance of the
amino alcohol, the crude product was purified by column
chromatography to give the corresponding pyrazine products
8 b–d[26, 27] (Table 2).
Although mechanistic studies have not been carried out,
we believe that first, OH activation of the alcohol by
complexes 1 or 2 results in aromatization of the pincer
complex. Then H2 liberation leads to the formation of a
coordinated aldehyde complex. A sequence involving nucleophilic attack by the amine group of a second amino alcohol
molecule on the aldehyde, which is coordinated to the PNN
complex 1, would eventually result in a peptide. In the case of
the bulky PNP complex 2, which lacks a hemilabile amine
“arm”, dissociation of the aldehyde and attack on it by the
amino alcohol take place in solution, resulting in an imine (by
water liberation from a hemiaminal), eventually leading to a
2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 12240 –12244
pyrazine after aromatization of a presumed 1,4-dihydropyrazine intermediate.
In summary, a new method for peptide-bond formation, in
particular selective formation of cyclic dipeptides, and of
poly(alanine), was developed using dehydrogenative selfcoupling of b-amino alcohols. The reactions are catalyzed by
the dearomatized PNN complex 1 and lead to a variety of
biologically important cyclic dipeptides. In striking contrast,
the closely related dearomatized PNP complex 2 selectively
catalyzes the dehydrogenative coupling of b-amino alcohols
to form pyrazines. These unprecedented reactions proceed
under neutral reaction conditions and generate no waste,
thereby representing a clear departure from traditional
synthetic methodology.
Received: August 19, 2011
Revised: October 4, 2011
Published online: October 26, 2011
Keywords: dehydrogenation · homogeneous catalysis ·
peptides · pyrazines · ruthenium
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